Systemic associations of retinal microvascular signs: a review of recent population-based studies

Retinal microvascular signs, such as generalized retinal arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking and retinal haemorrhages, microaneurysms and cotton wool spots, are common fundus findings in the general population, even in individuals without hypertension or diabetes. Recent population-based studies have provided new insights into the systemic associations and clinical significance of these retinal signs. Studies show that these retinal microvascular signs are strongly associated with elevated blood pressure (BP). Generalized retinal arteriolar narrowing may be associated with markers of inflammation and risk of diabetes and hypertension. Retinal haemorrhages, microaneurysms and cotton wool spots are associated with risk of subclinical and clinical stroke, cognitive impairment, renal dysfunction and cardiovascular mortality, independent of BP and cardiovascular risk factors. A consistent pattern of association between retinal microvascular signs and ischaemic heart disease has not been demonstrated. This suggests that patients with some retinopathy signs (retinal haemorrhages, microaneurysms and cotton wool spots) may benefit from a careful systemic evaluation and, if supported by further research, appropriate risk reduction therapy.     

Retinal vessel diameters and incident open-angle glaucoma and optic disc changes: the Rotterdam study

PURPOSE: It remains unclear whether reduced retinal blood flow and smaller arterioles, reported to exist in patients with open-angle glaucoma (OAG), are a cause or a consequence of ganglion cell loss. We examined whether baseline retinal vessel diameters were related to incident (i)OAG or incident optic disc changes in a population-based sample. METHODS: In the prospective population-based Rotterdam Study, baseline diameters of retinal arterioles and venules (1990-1993) were measured in digitized images of 3469 persons (aged 55 years and older) at risk for OAG. The follow-up examinations took place from 1997 to 1999. iOAG was based on the presence of incident glaucomatous visual field loss and/or incident glaucomatous optic neuropathy. Changes in neuroretinal rim, cup area, or vertical cup-to-disc ratio were calculated with a semiautomated image analyzer in 2782 persons. RESULTS: After a mean follow-up time of 6.5 years, 74 participants had iOAG. At baseline, the mean arteriolar diameter was 147.5 +/- 14.2 microm (SD) and the venular, 222.9 +/- 20.0 microm. Neither arteriolar diameters (odds ratio [OR] per SD decrease: 0.82; 95% confidence interval [CI]: 0.66-1.03) nor venular ones (OR per SD increase: 1.20; 95% CI: 0.95-1.53) were significantly related to iOAG. Baseline retinal vessel diameters did not predict changes in the optic disc. Additional adjustment for cardiovascular risk factors did not alter these results. CONCLUSIONS: The data show that baseline retinal vessel diameters did not influence the risk of iOAG or incident optic disc changes. These data provide no evidence for a retinal vascular role in the pathogenesis of OAG.     

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness.     

Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality

Retinal microvascular abnormalities, such as generalized and focal arteriolar narrowing, arteriovenous nicking and retinopathy, reflect cumulative vascular damage from hypertension, aging, and other processes. Epidemiological studies indicate that these abnormalities can be observed in 2-15% of the nondiabetic general population and are strongly and consistently associated with elevated blood pressure. Generalized arteriolar narrowing and arteriovenous nicking also appear to be irreversible long-term markers of hypertension, related not only to current but past blood pressure levels as well. There are data supporting an association between retinal microvascular abnormalities and stroke, but there is no convincing evidence of an independent or direct association with atherosclerosis, ischemic heart disease, or cardiovascular mortality. New computer-related imaging methods are currently being developed to detect the presence and severity of retinal arteriolar narrowing and other microvascular characteristics. When reliably quantified, retinal microvascular abnormalities may be useful as risk indicators for cerebrovascular diseases.     

Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors

OBJECTIVE: Narrowed retinal arterioles may independently predict cardiovascular disease. We describe a computer-assisted method to measure retinal vessel diameters from digitized fundus photographs in a large population, and examine the correlation of retinal vessel diameters between eyes and whether refractive errors affect these measurements. DESIGN AND POPULATION: Population-based, cross-sectional study in Beaver Dam, Wisconsin (n = 4926; age, 43-84 years). METHODS: Retinal photographs were digitized, and all arterioles and venules located in an area 0.5 to 1 disc diameter from the optic disc were measured with the aid of computer software. MAIN OUTCOME MEASURES: Summary of retinal arteriolar and venular diameters, and the ratio of their diameters (arteriole:venule ratio [AVR]). RESULTS: Correlation between right and left eyes was substantial for retinal arteriolar diameters (Pearson correlation coefficient, rho = 0.71) and venular diameters (rho = 0.74), and moderate for the AVR (rho = 0.49). The inverse association of higher blood pressure and smaller retinal arteriolar diameters was similar using data from either one eye or two eyes; arteriolar diameters decreased by 4.1 microm (right eyes), 4.0 microm (left eyes), and 4.0 microm (mean of both eyes) with each 10-mmHg increase in mean arterial blood pressure. A myopic refraction was associated with smaller retinal vessel diameters; arteriolar diameters decreased by 2.8 microm and venular diameters by 3.3 microm with each -1.0-diopter shift towards myopia. However, the pattern and strength of the association of blood pressure and retinal vessel diameters were not altered by variations in refractive errors. CONCLUSIONS: There is good correlation of retinal vessel diameters between eyes. A myopic refraction is associated with smaller retinal vessel diameters. The association of retinal arteriolar diameters and blood pressure seems similar using data from either one eye or two eyes, and is minimally affected by refraction. These data suggest that measurement of retinal vessel diameters from one eye without regard to its refractive status may provide adequate information indicative of a person's retinal vessel caliber if information from two eyes and refraction is unavailable.     

Coats病的诊断与治疗进展

Coats病又称为外层渗出性视网膜病变,它是一种以视网膜毛细血管和微血管异常扩张为特征,并常伴有视网膜内或视网膜下脂质渗出及渗出性视网膜脱离的疾病,晚期可并发新生血管性青光眼甚至眼球萎缩.Coats病在临床表现与形态学上具有显著的多样性,近一个世纪以来,随着对该病认识地不断深入,国内外玻璃体视网膜专家对Coats病的诊断与治疗也产生了新的看法,本文将着重对Coats病的诊断与治疗进展作一综述.     

视网膜微循环检测技术及其临床应用

各种眼部疾病,尤其是视网膜疾病均可改变视网膜微血管状态。此外,涉及全身血管系统改变的疾病如心血管疾病等也存在视网膜微循环改变。因此视网膜微血管系统的改变除了主要作为眼部疾病的辅助诊断指标外,还有助于评价全身性疾病,是重要的疾病指标。本文简要综述了视网膜微循环检查的检测方法及各项检测方法的临床应用现状。     

中药单体干预糖尿病视网膜神经退行性变的研究进展

糖尿病视网膜病变(DR)传统意义上被认为是视网膜的单纯微血管疾病,目前主流疗法仍然只关注其晚期血管病变并发症和单一分子靶点-血管内皮生长因子(VEGF)。然而现在研究正转向一个更全面的观点,即DR是神经血管单元(NVU)损伤引起的一类神经血管性疾病。在DR早期阶段,糖尿病视网膜神经退行性变(DRN)占主导地位,可能先于微血管异常发生,且神经元细胞的凋亡可进一步导致微血管损伤和血-视网膜屏障(BRB)破坏。因此在早期DR中开发新的治疗策略来预防或逆转DRN是有意义的,然而目前尚没有针对DRN的药物被批准用于临床。近年来研究中药对视网膜保护作用已成为热点,且主要研究集中在中药单体。本文综述了具有代表性的中药单体在DRN中的研究现状,以期为DR的早期治疗与新药研发提供参考。     

视网膜静脉阻塞机制及危险因素研究进展

视网膜静脉阻塞(RVO)是第二大视网膜血管疾病，其病理生理机制复杂，除血管机械压迫外，炎症和内皮素也都被证实参与RVO的发病，但具体机制尚不明确。既往文献证明高血压、糖尿病和血脂异常是老年人群中最常见的危险因素，而近期研究发现凝血异常和血液流变学异常在50岁以下人群中更为常见。眼部危险因素也越来越受到重视，包括青光眼、高校正眼压及眼底血管异常。不同危险因素间存在协同关系，早期识别并且干预能有效降低RVO的发病率。本文旨在对近期相关研究进行综述，对现有机制理论进行总结，为发掘潜在药物靶点提供研究思路，同时为疾病危险因素识别和管理提供参考。     

Relationships between age,blood pressure,and retinal vessel diameters in an older population

PURPOSE: To describe the cross-sectional relationships between age, blood pressure (BP), and quantitative measures of retinal vessel diameters in an older Australian population. METHODS: Retinal photographs from right eyes of participants (n = 3654, aged 49+ years) in the Blue Mountains Eye study taken during baseline examinations (1992-1994) were digitized. The width of all retinal vessels located 0.5 to 1.0 disc diameters from the disc margin was measured by a computer-assisted method. Summarized estimates for central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) represent average retinal vessel diameters. The arteriole-to-venule ratio (AVR) was calculated. Associations between age and BP and CRAE, CRVE, and AVR were assessed with generalized linear models. RESULTS: Retinal vessel diameters decreased with increasing age in both men and women. CRAE and CRVE decreased by 4.8 microm and 4.1 microm, respectively, per decade increase in age, after adjusting for sex and mean arterial blood pressure. Mean AVR declined by 0.01 for each increasing decade of age, until 79 years. After adjustment for age, sex, smoking, and body mass index, CRAE, CRVE and AVR were all significantly and inversely associated with BP. For every 10-mm Hg increase in mean arterial blood pressure, AVR decreased by 0.012 and CRAE and CRVE decreased by 3.5 microm and 0.96 microm, respectively. CONCLUSIONS: Retinal arteriolar and venular diameters narrow with increasing age, and these parameters are inversely related to BP, independent of age, gender, and smoking. The findings are consistent with those from the Atherosclerosis Risk in Communities Study suggesting that decreased retinal vessel diameters may reflect microvascular damage from elevated blood pressure.     

The association between retinal vasculature changes and stroke: a literature review and Meta-analysis

AIM: To determine the association between retinal vasculature changes and stroke. METHODS: MEDLINE and EMBASE were searched for relevant human studies to September 2015 that investigated the association between retinal vasculature changes and the prevalence or incidence of stroke; the studies were independently examined for their qualities. Data on clinical characteristics and calculated summary odds ratios (ORs) were extracted for associations between retinal microvascular abnormalities and stroke, including stroke subtypes where possible, and adjusted for key variables. RESULTS: Nine cases were included in the study comprising 20 659 patients, 1178 of whom were stroke patients. The retinal microvascular morphological markers used were hemorrhage, microaneurysm, vessel caliber, arteriovenous nicking, and fractal dimension. OR of retinal arteriole narrowing and retinal arteriovenous nicking and stroke was 1.42 and 1.91, respectively, indicating that a small-caliber retinal arteriole and retinal arteriovenous nicking were associated with stroke. OR of retinal hemorrhage and retinal microaneurysm and stroke was 3.21 and 3.83, respectively, indicating that retinal microvascular lesions were highly associated with stroke. Results also showed that retinal fractal dimension reduction was associated with stroke (OR: 2.28 for arteriole network, OR: 1.80 for venular network). CONCLUSION: Retinal vasculature changes have a specific relationship to stroke, which is promising evidence for the prediction of stroke using computerized retinal vessel analysis.     

Innovations in the treatment of the macular edema in retinal venous occlusions

The authors present new possibilities in the treatment of the macular edema caused by the retinal venous occlusions; these occlusions are the second most common retinal vessel disease. The earlier possibilities of the treatment were focused on the macular edema laser treatment, laser panretinal photocoagulation in case of retinal or iris neovascularization presence, and the disease's risk factors compensation. In the presence, the intravitreal application of corticosteroids or anti VEGF A preparations are more used for the treatment because of better results, as proved by means of randomized, clinical studies.     

糖尿病视网膜血管病变中未折叠蛋白反应:蛋白质折叠的意义和治疗潜力

血管生成是由多因素共同参与调节,涉及正常的胚胎发育以及出生后的一种复杂的病理过程,如癌症、心血管疾病和糖尿病。而糖尿病视网膜病变（diabetic retinopathy,DR）则是眼科疾病中常见的糖尿病微血管病变,其中视网膜和脉络膜异常的血管生长是导致视力丧失的主要原因,它与血管变性、缺血、视网膜组织血管重构互为因果并动态关联。了解视网膜新生血管的机制,研发具有创新性的治疗方案是今后努力的方向。越来越多的证据表明,未折叠蛋白反应（unfold protein response,UPR）在调节血管生成方面扮演着非常重要的角色。本文总结了目前在视网膜内质网中的UPR相关研究以及UPR在DR新生血管形成和血管重构的信号,强调这些应激反应途径在预防和治疗导致视力缺陷和失明的DR中的潜在意义。     

Review of the association between retinal microvascular characteristics and eye disease

Computerized retinal imaging technologies enable the static and dynamic measurement of a range of retinal microvascular parameters. Large population‐based studies have reported associations between these microvascular indices and various ophthalmic diseases including diabetes, age‐related macular degeneration, retinal artery embolism, retinal vein occlusion, glaucoma and non‐glaucomatous optic neuropathies. Increasingly, sophisticated imaging and analysis techniques have the potential to provide relevant clinical information regarding disease risk and progression; however, further studies are required to verify associations and strengthen the predictive power of these techniques. We summarize the current state of knowledge regarding retinal microvascular characteristics and eye disease.     

Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study

PURPOSE: Retinal microvascular abnormalities reflect persistent arteriolar damage from hypertension and independently predict stroke. We examined their associations with long-term cardiovascular mortality. DESIGN: Population-based, nested, case-control study. POPULATION: Cases were Beaver Dam Eye Study participants (age range, 43-84 years) who died of coronary heart disease or stroke between the baseline examination in 1988 to 1990 and 1999 (n = 413). Nearly 3 controls per case were selected from the baseline cohort, frequency-matched on 5-year age intervals and gender (n = 1198). METHODS: Retinal photographs of cases and controls at baseline were evaluated for retinopathy, focal arteriolar narrowing, and arteriovenous nicking by graders masked to case-control status using standardized protocols. To obtain an estimate of generalized arteriolar narrowing, photographs were digitized and diameters of individual retinal vessels were measured and summarized by a computer program. MAIN OUTCOME MEASURE: Ten-year cardiovascular mortality. RESULTS: After controlling for systolic blood pressure, diabetes, glycosylated hemoglobin levels, and other risk factors, retinopathy was associated with increased cardiovascular mortality, with odds ratios of 1.8 (95% confidence interval [CI], 1.2, 2.7). For other retinal abnormalities, associations with cardiovascular mortality were present only in younger people, with odds ratios of 2.7 (95% CI, 1.0, 7.4) for focal arteriolar narrowing, 1.8 (95% CI, 0.8, 4.5) for arteriovenous nicking, and 1.9 (95% CI, 1.2, 2.9) for generalized arteriolar narrowing in persons 43 to 74 years of age but odds ratios of 1.1, 0.4, and 1.0 for the corresponding retinal abnormalities in persons 75 years and older. CONCLUSIONS: Retinopathy is independently associated with cardiovascular mortality. Associations for other retinal abnormalities were only observed in middle-aged persons. These data support recent studies that suggest retinal microvascular abnormalities provide independent information regarding cardiovascular risk.     

Heritability of retinal vessel diameters and blood pressure: a twin study

PURPOSE: To assess the relative influence of genetic and environmental effects on retinal vessel diameters and blood pressure in healthy adults, as well as the possible genetic connection between these two characteristics. METHODS: In 55 monozygotic and 50 dizygotic same-sex healthy twin pairs, aged 20 to 46 years, interpolated diameter estimates for the central retinal artery (CRAE), the central retinal vein (CRVE), and the artery-to-vein diameter ratio (AVR) were assessed by analysis of digital gray-scale fundus photographs of right eyes. RESULTS: The heritability was 70% (95% CI: 54%-80%) for CRAE, 83% (95% CI: 73%-89%) for CRVE, and 61% (95% CI: 44%-73%) for mean arterial blood pressure (MABP). Retinal artery diameter decreased with increasing age and increasing arterial blood pressure. Mean vessel diameters in the population were 165.8 +/- 14.9 microm for CRAE, 246.2 +/- 17.7 microm for CRVE, and 0.67 +/- 0.05 microm for AVR. No significant influence on artery or vein diameters was found for gender, smoking, body mass index (BMI), total cholesterol, fasting blood glucose, or 2-hour oral glucose tolerance test values. CONCLUSIONS: In healthy young adults with normal blood pressure and blood glucose, variations in retinal blood vessel diameters and blood pressure were predominantly attributable to genetic effects. A genetic influence may have a role in individual susceptibility to hypertension and other vascular diseases. The results suggest that retinal vessel diameters and the possible associated variations in risk of vascular disease are primarily genetic characteristics.     

Effects of sildenafil on retinal blood flow and flicker-induced retinal vasodilatation in healthy subjects

PURPOSE: Sildenafil is a specific inhibitor of phosphodiesterase V, which is widely used for the treatment of erectile dysfunction. Sildenafil has been shown to induce vasodilation in several vascular beds by inhibiting the cGMP breakdown. The present study was conducted to investigate whether sildenafil increases blood flow in the human retina. METHODS: In a randomized, double-masked, placebo-controlled, two-way crossover study in 12 healthy male volunteers the effects of a single dose of 100 mg sildenafil were studied. Subjects received sildenafil or placebo on two different study days. After administration, retinal hemodynamic parameters were measured every 20 minutes. Retinal vessel diameters and retinal blood velocity were assessed with the retinal vessel analyzer and bidirectional laser Doppler flowmetry, respectively. In addition, the response of retinal vessel diameters to stimulation with diffuse flicker light was studied. Blood pressure and intraocular pressure were measured with noninvasive techniques. RESULTS: Sildenafil had no effect on mean arterial pressure, pulse rate, intraocular pressure, retinal blood velocity, or retinal arterial diameter. However, a significant increase in retinal venous diameters (4.7% +/- 3.2%; P=0.0028 versus placebo) and retinal blood flow 15.7% +/- 18.0%; P=0.029 versus placebo) was observed. Sildenafil had no effect on flicker-induced vasodilation in retinal arteries or veins. CONCLUSIONS: The data indicate that sildenafil increases retinal venous diameters and retinal blood flow in healthy subjects. By contrast, it does not affect intraocular pressure and flicker-induced retinal vasodilation. Further studies are needed to elucidate whether this drug may be therapeutically used in retinal ischemic disease.     

Diabetische Makulopathie und Retinopathie

Objective

The incidence of diabetic microvascular complications is expected to increase by 20–50% in the coming years. Diabetic macular edema (DME) is already a leading cause of blindness in the working-age population in developed countries, and its impact is expected to increase dramatically.

Methods

Recent literature on the epidemiology and impact of diabetic microangiopathy (maculopathy) on visual function was reviewed to provide a comprehensive overview of the functional and socioeconomic consequences of diabetic retinal microangiopathy and new therapeutic strategies.

Results

The first changes indicating diabetic microangiopathy are detectable shortly after the development of hyperglycemia, and in the long term they induce severe organ damage. More resources are used for this condition’s treatment than for the treatment of hyperglycemia, corresponding to an enormous sociomedical burden of disease. Early detection of increased retinal vascular permeability may help control treatment effects. The control of recognized risk factors for the development and progression of DME, namely hyperglycemia and hyperlipidemia, as well as of hypertension has remained the cornerstone of therapy and serves as the basis for preserving visual function.

Conclusions

Modern treatment options, begun early, may result in a remarkably delayed occurrence of irreversible diabetic microvascular pathologies, particularly diabetic retinopathy and maculopathy. Ophthalmological screening nowadays aims at earlier recognition of at-risk individuals to optimize the therapeutic strategy—that is, before visual impairment is imminent. Close interdisciplinary medical cooperation and implementation of new therapeutic options may provide the foundation for success in terms of maintaining visual function.     

Adaptive optics imaging of the retinal microvasculature

The eye has long been recognised as the window to pathological processes occurring in the brain and other organs. By imaging the vasculature of the retina we have improved the scientific understanding and clinical best practice for a diverse range of conditions, ranging from diabetes, to stroke, to dementia. Mounting evidence suggests that damage to the smallest and most delicate vessels in the body, the capillaries, is the first sign in many vasculopathies. These are the most critical vessels involved in the exchange of metabolites with tissue. Accurate assessment of retinal capillary structure and function would therefore be of great benefit across a broad range of disciplines in medical science; however, their small size does not make this an easy task. This has led to the development of high-resolution adaptive optics imaging methods to non-invasively explore retinal microvascular networks in living human eyes. This review describes the present state of the art in the field, the scientific breakthroughs that have been made possible in the understanding of vessel structure and function in health and disease, and future directions for this emerging technology.     

Associations between the metabolic syndrome and retinal microvascular signs: the Atherosclerosis Risk In Communities study

PURPOSE: To examine the cross-sectional relationship of the metabolic syndrome (hypertension, hyperglycemia, central obesity, and dyslipidemia) and retinal microvascular abnormalities in middle-aged men and women. METHODS: A population-based, cross-sectional study involving 11,265 persons aged 49 to 73 years who had retinal photography from 1993 through 1995. Photographs were graded for presence of retinal microvascular signs (microaneurysms, retinal hemorrhages, arteriovenous nicking, and focal arteriolar narrowing) according to a standardized protocol. To quantify retinal vessel diameters, photographs were digitized and individual arteriolar and venular diameters were measured and summarized. The metabolic syndrome was defined according to the Third Report of the National Cholesterol Education Program Adult Treatment Panel. RESULTS: After adjustment for age, gender, race, education, cigarette smoking and alcohol consumption, persons with the metabolic syndrome were more likely to have retinopathy (odds ratio [OR] 1.68, 95% confidence interval [CI], 1.45-1.96), arteriovenous nicking (OR 1.30, 95% CI, 1.16-1.45), focal arteriolar narrowing (OR 1.24, 95% CI, 1.10-1.38), generalized retinal arteriolar narrowing (OR 1.23, 95% CI, 1.12-1.35), and generalized retinal venular dilatation (OR 1.30, 95% CI, 1.18-1.48) than persons without the metabolic syndrome. Associations for arteriovenous nicking, focal arteriolar narrowing, generalized arteriolar narrowing, and venular dilatation were noted, even in people without diabetes or hypertension. CONCLUSIONS: These data suggest that the metabolic syndrome is associated with microvascular changes in the retina. This finding reflects, in part, the associations of individual syndrome components with retinal microvascular abnormalities.